August 18th

Scientists are planning for a future in which superbugs gain the upper hand against our current arsenal of antibiotics. One emerging class of drug candidates, called AMLPs (antimicrobial lipopeptides), shows promise, and an article published in the August 18, 2015 issue of the Biophysical Journal explains why: they selectively kill bacterial cells, while sparing mammalian host cells, by clumping together into microscopic balls that stick to the bacterial membrane--a complex structure that will be slower to mutate and thus resist drugs. "The pressing need for novel antibiotics against resistant strains of bacteria and fungi has become a global medical concern," says senior study author Dr. Alan Grossfield of the University of Rochester Medical Center in New York. "Our new insights into how AMLPs work as groups, rather than individually, could optimize the development of these molecules as a new class of anti-resistance antibiotics." AMLPs could represent a promising alternative to traditional antibiotics. Past studies have shown that these synthetic compounds have potent activity against a range of pathogens and can clear infections in mice. Moreover, AMLPs are less vulnerable to evolved resistance because they disrupt the structure and function of microbial membranes. To evolve drug resistance, the microbes would require many big changes to alter the mixture of lipids composing the membrane. In addition, a variety of critical proteins embedded in the membrane depend on the membrane's current composition of lipids, so membrane changes that would prevent AMLP function would also tend to hinder the function of the bacteria's own membrane proteins. Despite their advantages, progress in developing AMLPs suitable for the clinic has been limited by the lack of a molecular-level understanding of their mode of action.

One major cause of human blindness is autoimmune uveitis, which is triggered by the activation of T cells, but exactly how and where the T cells become activated in the first place has been a long-standing mystery. A study, published as an open-access “Featured Article” in the August 18, 2015 issue of the journal Immunity, reveals that gut microbes produce a molecule that mimics a retinal protein, which most likely activates the T cells responsible for the disease. The article is titled “Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site." By shedding light on the cause of autoimmune uveitis in mice, the study could contribute to a better understanding of a broad range of autoimmune disorders and pave the way for novel prevention strategies in the future. "Given the huge variety of commensal bacteria, if they can mimic a retinal protein, it is conceivable that they could also mimic other self-proteins that are targets of inappropriate immune responses elsewhere in the body," says senior study author Dr. Rachel Caspi of the National Institutes of Health. "We believe that activation of immune cells by commensal bacteria may be a more common trigger of autoimmune diseases than is currently appreciated." Autoimmune uveitis, which accounts for up to 15% of severe visual handicap in the Western world, affects the working-age population and significantly affects public health. Patients often have detectable immune responses to unique retinal proteins involved in visual function, and these proteins can elicit the disease in animal models.

Each cell in a woman’s body (except egg cells) contains two X chromosomes. One of these chromosomes is switched off, in order to maintain appropriate gene dosage compensation with males who are XY. Dr. Hendrik Marks and Dr. Henk Stunnenberg, molecular biologists at Radboud University Nijmegen, Netherlands, together with the group of Dr. Joost Gribnau from Erasmus MC in Rotterdam, Netherlands, have shown the mechanism by which this inactivation is spread over the X chromosome, The scientific journal Genome Biology will publish the final results; and a provisional PDF was posted online on August 3, 2015. The article is titled “‘Dynamics of Gene Silencing During X Inactivation Using Allele-Specific RNA-Seq.” In terms of sex chromosomes, men have a single X chromosome, as well as a Y chromosome, whereas women have two copies of the X chromosome. A process called X inactivation makes sure that one of these X chromosomes becomes inactivated in females during early embryonic development. A random process determines which of the two is switched off. A nice example of X inactivation can be observed in the fur of female tortoiseshell and calico cats. The gene for fur coloration resides on the X chromosome, while each of the two X chromosomes codes for a different color: black or orange. In an orange “patch,” only the X chromosome encoding the orange color is active, while in the black “patches,” only the X chromosome encoding the black colour is active. During normal human embryo development, X inactivation in females takes place at a very early stage. Others had previously discovered that the molecule “Xist” is key during X inactivation. In order to further study this process, Dr. Marks and his colleagues used embryonic stem cells as a model system to study X inactivation.

Indiana University (IU) paleobotanist Dr. David Dilcher and colleagues in Europe have identified a 125 million- to 130 million-year-old freshwater plant as one of earliest flowering plants on Earth. The finding, reported online on August 17, 2015 in PNAS, represents a major change in the presumed form of one of the planet's earliest flowers, known as angiosperms. The article is titled “Montsechia, an ancient aquatic angiosperm.” "This discovery raises significant questions about the early evolutionary history of flowering plants, as well as the role of these plants in the evolution of other plant and animal life," said Dr. Dilcher, an Emeritus Professor in the IU Bloomington College of Arts and Sciences' Department of Geological Sciences. The aquatic plant, Montsechia vidalii, once grew abundantly in freshwater lakes in what are now mountainous regions in Spain. Fossils of the plant were first discovered more than 100 years ago in the limestone deposits of the Iberian Range in central Spain and in the Montsec Range of the Pyrenees, near the Spain's border with France. Also previously proposed as one of the earliest flowers is Archaefructus sinensis, an aquatic plant found in China. "A 'first flower' is technically a myth, like the 'first human,'" said Dr. Dilcher, an internationally recognized expert on angiosperm anatomy and morphology, who has studied the rise and spread of flowering plants for decades. "But based on this new analysis, we know now that Montsechia is contemporaneous, if not more ancient, than Archaefructus." He also asserted that the fossils used in the study were "poorly understood and even misinterpreted" during previous analyses. "The reinterpretation of these fossils provides a fascinating new perspective on a major mystery in plant biology," said Dr. Donald H.

On August 13, 2015, it was announced that The Human Proteome Organization had named Amanda Paulovich, M.D., Ph.D., as the winner of its 2015 Distinguished Achievement in Proteomic Sciences Award. “This is a great honor and a testament to the hard work of my interdisciplinary team over the past 12 years. It is really a team award,” said Dr. Paulovich, who is a member of Fred Hutchinson Cancer Research Center’s Clinical Research Division, Director of the Hutch’s Early Detection Initiative, and an Associate Professor in the Department of Medicine/Division of Oncology at the University of Washington School of Medicine in Seattle, Washington. The award recognizes a scientist for distinguished scientific achievements in the field of proteomics. It will be presented during the HUPO 2015 Vancouver CongressSeptember 27-September 30, 2015 (https://www.hupo.org/events/hupo-14th-annual-world-congress-vancouver-20...), the organization’s 14th annual worldwide meeting. Dr, Paulovich and her lab have played a major role in the development of an efficient, high-powered, precise method to detect and measure proteins in biological samples, called multiple reaction monitoring mass spectrometry *(MRM-MS). Named “Method of the Year” for 2012 by Nature Methods (http://www.nature.com/nmeth/journal/v10/n1/full/nmeth.2329.html), MRM-based proteomic assays have the potential to overcome a serious problem in biomedical research, i.e., a lack of reliable, standardizable tests for studying human proteins. Proteins carry out most biological functions in the body – including driving cancer –and are the targets of most drugs.

August 17th

Researchers at the Ruhr-Universität Bochum in Germany have debunked the theory that the left brain hemisphere is dominant in the processing of all languages. To date, it has been assumed that this dominance is not determined by the physical structure of a given language. However, the Bocum biopsychologists have demonstrated that both hemispheres are equally involved in the perception of whistled Turkish. Dr. Onur Güntürkün, Dr. Monika Güntürkün, and Dr. Constanze Hahn report on this in an open-access article in the August 17, 2015 issue of Current Biology. The article is titled “Whistled Turkish Alters Language Asymmetries.” The perception of all spoken languages; including those with clicks, written texts, and even sign language; involves the left brain hemisphere more strongly than the right one. The right hemisphere, on the other hand, processes acoustic information via slow frequencies, pitch, and melody. According to the current commonly held opinion, the asymmetry in language processing is not determined by the physical properties of a given language. "The theory can be easily verified by analyzing a language which possesses the full range of physical properties in the perception of which the right brain hemisphere is specialized," says Dr. Güntürkün. "We can count ourselves lucky that such a language exists, namely whistled Turkish." The Bochum team tested 31 inhabitants of Ku?köy, a village in Turkey, who speak Turkish and whistle it as well. Via headphones, these inhabitants were presented either whistled or spoken Turkish syllables. In some test runs, they heard different syllables in both ears, in other runs, the same syllables. They were asked to state which syllable they had perceived.

Over a 10-year period, the time that babies receive genetic testing after being diagnosed with diabetes has fallen from over four years to under two months. Pinpointing the exact genetic causes of sometimes rare forms of diabetes is revolutionizing healthcare for these patients. Babies with diabetes are now being immediately genetically tested for all possible 22 genetic causes, while previously they would only get genetic testing years after diabetes was diagnosed and then the genes would be tested one at a time. Crucially, this means that the genetic diagnosis is made early, giving the doctor information on how best to treat the patient and inform them of the medical problems the patients are likely to develop in the future. This is a paradigm shift in how genetic testing fits in with the patients' clinical symptoms. In the past, symptoms were used to select which gene would be tested. Now, the early comprehensive gene testing means that the genetic result predicts clinical features that have not yet developed. This new paradigm means doctors can anticipate the likely problems for their patients and put the appropriate care in place to reduce their impact. The Wellcome Trust- and Diabetes UK-funded study was published online on July 29, 2015 in an open-access article in The Lancet by a team led by the University of Exeter Medical School. The article reports the results of genetic testing for the 22 known genetic causes of neonatal diabetes in 1,020 patients over the past ten years. The article is titled “The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study.” During this 10-year period, the time for genetic testing after diabetes has fallen from over four years to under two months.

Researchers at Loyala University in Chicago have shown that exsomes isolated from invasive bladder cancer cell-conditioned media, or from patient urine or bladder barbotage samples, play a role in epithelial-to-mesenchymal transition (EMT), which is a biological process in which epithelial cells lose their epithelial characteristics and acquire a migratory, mesenchymal phenotype. In EMT, epithelial cells lose their cell polarity and cell–cell adhesion and gain migratory and invasive properties to to become mesenchymal stem cells. EMT has been implicated in the initiation of metastasis for cancer progression. The Loyola researchers conclude that their research represents both a new insight into the role of exosomes in transition of bladder cancer into invasive disease, as well as an introduction to a new platform for exosome research in urothelial cells. The new Loyala work was published online on August 17, 2015 in an open-access article in Oncogenesis. The article is titled “Urothelial Cells Undergo Epithelial-to-Mesenchymal Transition after Exposure to Muscle Invasive Bladder Cancer Exosomes.” According to the Loyala authors, “Bladder cancer is the fourth most common noncutaneous malignancy in the United States. Non-muscle-invasive bladder cancer accounts for approximately 70% of newly diagnosed bladder cancer cases, with the remaining 30% being muscle-invasive bladder cancer (MIBC). Although non-muscle-invasive bladder cancer patients have a high survival rate, the recurrence rate is high, and 10–20% of these patients progress to MIBC.

High-grade serous ovarian cancer often responds well to the chemotherapy drug carboplatin, but why it so frequently comes back after treatment has been a medical mystery. Now a team of UCLA researchers has discovered that a subset of tumor cells that don’t produce the protein CA125, a biomarker used to test for ovarian cancer, has an enhanced ability to repair their DNA and resist programmed cell death — which allows the cells to evade the drug and live long enough to regrow the original tumor. It’s that regenerative ability and their resistance to carboplatin therapy that make the cells so dangerous, said Dr. Deanna Janzen, the study’s first author, and a Senior Scientist in the G.O. Discovery Lab at UCLA. The study, which appeared online on August 3, 2015 in an open-access article in Nature Communications, showed that pairing the carboplatin chemotherapy with an experimental drug eliminates the deadly population of cells believed to be responsible for repopulating the tumor. The additional drug, birinapant, sensitizes the CA125-negative cells to the chemotherapy by restoring apoptosis, or programmed cell death, said Dr. Sanaz Memarzadeh (photo), a senior author of the study and a UCLA gynecologic cancer surgeon. The open-access Nature Communications article is titled “An Apoptosis-Enhancing Drug Overcomes Platinum Resistance in a Tumour-Initiating Subpopulation of Ovarian Cancer.” Combining chemotherapy and birinapant significantly improved disease-free survival in laboratory models of human ovarian cancer compared to using either therapy alone. This suggests that targeting the CA125-negative cells may improve outcomes in these high-grade serous cancers, the most common subtype of ovarian cancer, said Dr.

Tumor cells associated with pancreatic cancer often behave like communities by working with each other to increase tumor spread and growth to different organs. Groups of these cancer cells are better than single cancer cells in driving tumor spread, according to new research from the Perelman School of Medicine at the University of Pennsylvania (Penn) published online in Cancer Discovery on July 24, 2015. The article is titled “Pancreatic Cancer Metastases Harbor Evidence of Polyclonality.” Ben Stanger, M.D., Ph.D., a Professor in the Division of Gastroenterology at Perelman, and first author Ravi Maddipati, M.D., an Instructor in the Division of Gastroenterology, say that these results may prove useful in designing better targeted therapies to stop tumor progression and to provide an improved non-invasive method for detecting early disease states in this highly lethal cancer. Dr. Stanger is also a Professor in the Department of Cell and Developmental Biology and the Abramson Family Cancer Research Institute. Cancer genome studies have shown that within most tumors there exist many different types of cells, which often harbor unique genetic alterations that lead to differences in their physiological properties. Previous studies using tumor cells lines suggested that these different tumor cell types may interact with each other to produce a more aggressive type of cancer. However, the mechanisms by which tumor cells interact to enhance the spread of cancer remained unclear. From other earlier studies, the Penn team also knew that cells from a primary tumor do better replicating and surviving in a group than they do if they are grown on their own. From this, the researchers asked if the spread of cancer is primarily derived from one cell or a cell cluster derived from the interactions between and among different cancer cell types. Dr.